CN110623927A - High-bioavailability nintedanib nano lipid carrier and preparation method thereof - Google Patents
High-bioavailability nintedanib nano lipid carrier and preparation method thereof Download PDFInfo
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- CN110623927A CN110623927A CN201810704226.8A CN201810704226A CN110623927A CN 110623927 A CN110623927 A CN 110623927A CN 201810704226 A CN201810704226 A CN 201810704226A CN 110623927 A CN110623927 A CN 110623927A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
The invention discloses a high-bioavailability nintedanib nano lipid carrier and a preparation method thereof. The nano lipid carrier comprises nintedanib, a solid lipid material, a liquid lipid material, a surfactant and an absorption enhancer. The preparation scheme comprises the following steps: heating solid and liquid lipid in water bath at certain temperature, and stirring to melt. Adding surfactant, and stirring for 5 min. Adding nintedanib, and stirring for 1 hr to obtain oil phase containing medicine. Adding part or all of surfactant into water phase, preheating at the same temperature, and adding water phase into the above oil phase under stirring. And (5) after the probe is subjected to ultrasonic treatment, solidifying in ice-water bath to obtain the product. The Nintedanib nano lipid carrier prepared by the method has the advantages of simple scheme, no organic solvent, high drug loading rate, uniform particle size and particle size distribution, good stability, and capability of remarkably increasing the absorption of small intestinal epithelial cells to Nintedanib and effectively improving the in vivo bioavailability.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations and the technical field of biological medicines, in particular to a high-bioavailability nintedanib nano lipid carrier and a preparation method thereof.
Background
Idiopathic pulmonary interstitial fibrosis (IPF) is a group of diseases characterized by progressive dyspnea and deterioration of lung function, of unknown etiology. Currently, there is no definitive and effective treatment for IPF other than lung transplantation. Without lung transplantation, their 3-and 5-year mortality rates were 50% and 80%, respectively.
Nintedanib is a triple tyrosine kinase inhibitor and a growth factor antagonist, is used for treating idiopathic pulmonary fibrosis diseases which can only be treated by lung transplantation in the medical field at present, and is a new research result for treating IPF. The nintedanib is a p-gp substrate, has a first-pass effect, is poor in solubility in a small intestine environment and not easy to absorb, and therefore the bioavailability of the nintedanib is low and is only 4.7% in vivo. Therefore, the search for a new dosage form that can effectively promote the oral bioavailability of nintedanib has long been a problem that is desired to be solved.
The existing products of the nintedanib are soft capsules sold in the company of the German Boringer Vargohne, and the products are prepared into solid dispersions to improve the bioavailability of the nintedanib through domestic and foreign researches. The nanometer lipid carrier is a new generation of nanometer medicine carrying system developed on the basis of solid lipid nanometer particles, and consists of solid and liquid mixed lipid, a surfactant and a medicine. As a nano drug carrier, the nano drug carrier can change the membrane transport mechanism, enhance the permeability of the drug to a biological membrane, and is beneficial to the percutaneous or mucosal permeation and absorption of the drug and the exertion of the drug effect in cells. The nano lipid carrier has good biocompatibility, can control the release of the drug, avoids the degradation or leakage of the drug, has good targeting property, and can be used for various administration routes.
Disclosure of Invention
Aiming at solving the problem of low oral bioavailability of nintedanib, the invention provides a curcumin nano lipid carrier with high bioavailability and a preparation method thereof.
The invention is realized by the following technical scheme:
a high bioavailability Nintedanib nanometer lipid carrier is characterized in that the raw material drug is Nintedanib, and the auxiliary materials comprise a solid lipid material, a liquid lipid material, a surfactant and an absorption enhancer. Wherein the contents of the components in 10ml of the final preparation are as follows: 50-200mg of nintedanib, 500-1500mg of solid lipid material, 750mg of liquid lipid material and 1000mg of surfactant.
The solid lipid material comprises glycerol trilaurate, glycerol monostearate, glycerol monooleate and glycerol behenate, preferably one or more of glycerol monooleate and glycerol trilaurate vinegar.
The liquid lipid material comprises tricaprylin, caprylic/capric triglyceride, medium-chain oil, poly-oleic glyceride, oleic acid, soybean oil and caprylic/capric polyethylene glycol glyceride, the mass of the liquid lipid material is one half of that of solid lipid, and one or more of tricaprylin and caprylic/capric polyethylene glycol glyceride are preferably selected.
The surfactant comprises phospholipid, tween-80, poloxamer 188, polyoxyethylene castor oil, lauric acid macrogol glyceride, polyvinyl alcohol and pluronic P85, and preferably one or more of tween-80, polyoxyethylene castor oil, poloxamer 188 or pluronic P85.
The invention also provides a preparation method of the nintedanib nano lipid carrier, which is characterized by comprising the following steps of:
the solid lipid material and the liquid lipid material are put in a water bath or an oil bath at the temperature of 10-40 ℃ higher than the melting point of the solid lipid material, and stirred at 600rpm/min until being melted.
Adding surfactant, and stirring for 5 min.
Adding nintedanib, and stirring for 1 hr to obtain oil phase containing medicine.
Adding 10-30% or all of surfactant into water phase, preheating at the same temperature, adding water phase into the oil phase obtained in the step (3) under stirring, and continuously stirring for 3 min.
Performing ultrasonic treatment on the probe for 5-15min under the power of 25-35%.
Curing in ice water bath for 5-10 min.
The temperature in step (1) is 30 ℃ higher than the solid lipid material.
The step (4) is to add 20% or all of the surfactant to the aqueous phase.
The power of the ultrasound in the step (5) is 30%.
The ultrasonic treatment time in the step (5) is 13 min.
The curing time in the step (6) is 6 min.
The average grain diameter of the nano lipid carrier is 10-200 nm.
The Nintedanib nano lipid carrier prepared by the method provided by the invention can obviously improve the in-vivo bioavailability of the Nintedanib and effectively improve the absorption of intestinal epithelial cells to the Nintedanib nano lipid carrier.
Drawings
Fig. 1 is a graph of blood drug concentration-time curve of nintedanib drug substance.
Fig. 2 is a blood concentration-time curve of the nintedanib nano lipid carrier.
Detailed description of the preferred embodiments
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the claims.
Example 1:
1250mg of glyceryl monooleate and 625mg of glyceryl tricaprylate are weighed into a small beaker, placed in a water bath at 67 ℃ and stirred at 600rpm/min until molten. Tween-80660 mg was added, and stirring was continued for 5 min. Adding 50mg of nintedanib, and stirring for 1h to obtain the oil phase containing the medicine. And taking a proper amount of distilled water, adding 225mg of Tween-80, and preheating at the same temperature to obtain a water phase. Slowly adding the water phase into the oil phase, and stirring for 3 min. Carrying out 30% power ultrasound for 13min, and carrying out ice bath curing for 6min to obtain the high-bioavailability nintedanib nano lipid carrier.
As a result: the particle size of the high bioavailability Nintedanib nano lipid carrier is 145.4 +/-3.1 nm. The encapsulation efficiency is 87.5 percent, and the drug loading rate is 5 mg/ml.
Example 2:
referring to the preparation method of example 1, except that the solid lipid material is selected from glycerol trilaurate, glycerol monostearate and glycerol behenate.
Table 1 effect of solid lipids on high bioavailability nintedanib lipid vehicle (n ═ 3)
Example 3:
referring to the preparation method of example 1, except that the liquid lipid material was selected from caprylic capric triglyceride, medium-chain oil, poly-oleic glyceride, oleic acid, soybean oil and caprylic capric polyglycol glyceride, respectively.
TABLE 2 Effect of liquid lipids on high bioavailability Nintedanib lipid vehicle (n ═ 3)
Example 4:
referring to the preparation method of example 1, except that the surfactant is one or more selected from poloxamer 188, polyoxyethylene castor oil, lauric acid macrogol glyceride, polyvinyl alcohol and pluronic P85.
Table 3 effect of surfactants on high bioavailability nintedanib lipid vehicles (n ═ 3)
Example 5:
referring to the preparation method of example 1, except that the surfactants are preferably tween-80 and poloxamer 188 respectively, the ratio of tween-80 to poloxamer 188 is changed to 3: 1, 2: 1, 1: 2 and 1: 3 when the surfactants are used in combination.
Table 4 effect of surfactant ratio on high bioavailability nintedanib lipid carrier (n ═ 3)
Example 6
Referring to the preparation method of example 1, except that the mass of nintedanib was changed to 100mg, 150mg, and 200mg, respectively.
TABLE 5 Effect of drug loading on high bioavailability Nintedanib lipid vehicle (n ═ 3)
Example 7:
the pharmacokinetics comparison of the nintedanib nano lipid carrier and the nintedanib bulk drug:
SD rats (male, body weight 200-. Fasting was overnight before dosing, and water was freely available. The nintedanib nano lipid carrier obtained in example 1 and the nintedanib bulk drug suspension are taken as examples, and the same dose (30mg/kg) is respectively administered by intragastric administration. Respectively taking blood from orbital venous plexus at 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h and 24h after administration, placing in a centrifuge tube with heparin sodium, and centrifuging at 8000rpm/min to obtain plasma. 100 μ L of the obtained plasma was taken, 20 μ L of the internal standard solution (2.5 μ g/ml) was added, and vortexed and shaken for 3 min. Adding ethyl acetate 1ml, vortexing for 5min, centrifuging at 10000rpm/min for 10min, sucking supernatant nitrogen gas for drying, redissolving 100 μ L of mobile phase, vortexing for 5min, centrifuging at 12000rpm/min for 10min, taking supernatant, and injecting 10 μ L. The mass spectrum and chromatographic conditions are as follows by using UPLC-MS/MS analysis and determination:
conditions of Mass Spectrometry
An ion source: ESI source positive ionization mode; capillary pressure: 2.0 kV; ion source temperature: 100 ℃; desolvation temperature: 400 ℃; flow rate of desolventizing agent: 550L/h; taper hole air flow rate: 50L/h; the scanning mode is as follows: multiple reactive ion monitoring (MRM) mode. Mass spectral parameters for the determination of BIBF and IS are shown in Table 1.
TABLE 6 Mass Spectrometry parameters of DSF and IS
Chromatographic conditions
ACQUITYTM UPLC system (Waters Corp., Milford, MA, USA); phenomenex kinetex XB C18 column (50mm X21 mm, 2.6 μm; Phenomenex, Torrance, CA, USA); column temperature: 40 ℃; autosampler temperature: 4 ℃; sample introduction amount: 10 mu L of the solution; sample introduction mode: partial sample introduction (partial loop mode); mobile phase: acetonitrile (a) and water (containing 0.1% formic acid) (B) 70: 30.
Results plasma concentration-time of both formulationsThe curves are shown in fig. 1-2. The AUC is 901.606 ug/Lxh and 394.29 ug/Lxh respectively, and the relative bioavailability is calculated according to the AUC of the two preparationsT·DR/AUCR·DT×100％＝(901.606*30)/(394.29*30)*100％＝228.67％
Where AUC represents the area under the plasma concentration-time curve, the subscripts T and R represent the test formulation and the extravascularly administered reference formulation, respectively, and D represents the administered dose.
It can be seen that the bioavailability of the nintedanib nano lipid carrier can be more than twice of that of the nintedanib raw material drug, and the bioavailability of the nintedanib in vivo can be effectively improved.
Claims (10)
1. A high bioavailability Nintedanib nanometer lipid carrier is characterized in that the raw material drug is Nintedanib, and the auxiliary materials comprise a solid lipid material, a liquid lipid material, a surfactant and an absorption enhancer; wherein the contents of the components in 10ml of the final preparation are as follows: 50-200mg of nintedanib, 500-1500mg of solid lipid material, 750mg of liquid lipid material and 1000mg of surfactant.
2. The highly bioavailable nintedanib liposomal carrier of claim 1, wherein: the solid lipid material comprises glycerol trilaurate, glycerol monostearate, glycerol monooleate and glycerol behenate, preferably one or more of glycerol monooleate and glycerol trilaurate vinegar.
3. The highly bioavailable nintedanib liposomal carrier of claim 1, wherein: the liquid lipid material comprises tricaprylin, caprylic/capric triglyceride, medium-chain oil, poly-oleic glyceride, oleic acid, soybean oil and caprylic/capric polyethylene glycol glyceride, the mass of the liquid lipid material is one half of that of solid lipid, and one or more of tricaprylin and caprylic/capric polyethylene glycol glyceride are preferably selected.
4. The highly bioavailable nintedanib liposomal carrier of claim 1, wherein: the surfactant comprises phospholipid, tween-80, poloxamer 188, polyoxyethylene castor oil, lauric acid macrogol glyceride, polyvinyl alcohol and pluronic P85, and preferably one or more of tween-80, polyoxyethylene castor oil, poloxamer 188 or pluronic P85.
5. The nedanib nanoliposome carrier according to any one of claims 1-4, wherein the nanoliposome carrier is prepared by the following method:
(1) the solid lipid material and the liquid lipid material are put in a water bath or an oil bath at the temperature of 10-40 ℃ higher than the melting point of the solid lipid material, and are stirred at 600rpm/min until being melted;
(2) adding surfactant, and stirring for 5 min;
(3) adding nintedanib, and continuously stirring for 1h to obtain a drug-containing oil phase;
(4) adding 10-30% or all of surfactant into water phase, preheating at the same temperature, adding water phase into the oil phase obtained in the step (3) under stirring, and continuing stirring for 3 min;
(5) performing ultrasonic treatment on the probe for 5-15min under the power of 25-35%;
(6) curing in ice water bath for 5-10 min.
6. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the temperature in step (1) is 30 ℃ higher than the solid lipid material.
7. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the step (4) is to add 20% or all of the surfactant to the aqueous phase.
8. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the power of the ultrasound in the step (5) is 30%.
9. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the ultrasonic treatment time in the step (5) is 13 min.
10. The method for preparing the nintedanib nano-lipid carrier according to claim 5, wherein the carrier comprises: the curing time in the step (6) is 6 min.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111973596A (en) * | 2020-06-15 | 2020-11-24 | 深圳市泰力生物医药有限公司 | Anti-pulmonary fibrosis composition with improved dissolution property |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111973596A (en) * | 2020-06-15 | 2020-11-24 | 深圳市泰力生物医药有限公司 | Anti-pulmonary fibrosis composition with improved dissolution property |
| CN111973596B (en) * | 2020-06-15 | 2022-02-15 | 深圳市泰力生物医药有限公司 | Anti-pulmonary fibrosis composition with improved dissolution property |
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